CARMA3 Promotes Colorectal Cancer Cell Motility and Cancer Stemness via YAP-Mediated NF-κB Activation

SIMPLE SUMMARY: CARMA3 is overexpressed in most cancers, and its expression is positively associated with poor prognosis. In this study, we evaluated the detailed mechanisms of CARMA3-mediated CRC metastasis. We found that overexpression of CARMA3 induced the expression of YAP and NF-κB activation, then elicited EMT induction to enhance cell migration and invasion. We demonstrate for the first time that YAP is a critical downstream regulator of CARMA3 in CRC. Our findings reveal a regulation axis between CARMA3 and Hippo oncoprotein YAP and further support the potential role of CARMA3 in the metastasis and cancer stemness of CRC. ABSTRACT: CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.